How is antigen loss managed in chimeric antigen receptor (CAR) T-cell therapy?

Updated: May 04, 2018
  • Author: Sameh Gaballa, MD, MS; Chief Editor: Emmanuel C Besa, MD  more...
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Answer

The FDA currently has 76 active investigational new drug applications related to CAR T-cell products under review. [10]  Some of these products address limitations of anti-CD19 therapy, while others expand CAR T-cell therapy to other indications. For example, patients who have received CAR T-cell therapy for ALL may experience recurrent disease because of antigen loss—their leukemia cells no longer express CD19.

One approach to this problem has been CAR T-cell therapy directed against CD22, which ALL cells often over-express. In a phase I study of relapsed or refractory B-cell ALL in nine patients (age range, 7-22 y)—six of whom had experienced antigen loss after anti-CD19 therapy—anti-CD22 CAR T-cell therapy proved safe and feasible, and demonstrated clinical activity. Four patients attained a complete marrow remission, all of whom were minimal residual disease (MRD) negative. [29]

An alternative strategy to deal with antigen loss is the use of dual targeting as initial therapy. CAR T-cells that target both CD19 and CD22 are under development, [2]  and initial research suggests that use of CAR T-cells that target both CD19 and CD123, another antigen commonly found on leukemia cells, may prevent antigen loss. [30]

In summary, current CAR T-cell therapies represent a major advance in the treatment of B-cell malignancies as well as a paradigm for future efforts directed at other currently incurable tumor types. CAR T-cell use can be associated with severe and even life-threatening side effects, but these toxicities must be viewed in the context of the risk-benefit ratio for the very aggressive, refractory, and life-threatening malignancies for which CAR T-cells are currently indicated or being explored. Fortunately, with experience, these toxicities can be ameliorated. One may reasonably hope that over the next few years, new and effective applications of this exciting treatment modality will emerge.


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